Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.23.5 (cathepsin D)
4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The properties and subcellular localization of the elastase-like activities of smooth muscle cells cultured from pig aortas have been investigated. Homogenates of the cells hydrolysed N-succinyl-L-alanyl-L-alanyl-L-alanine-p-nitroanilide, a synthetic substrate for elastases, with a distinct pH optimum of 8.2 and hydrolysed insoluble elastin with a distinct pH optimum of 8.5. Both enzyme activities were directly proportional to the concentration of homogenate in the assay mixture. The activities toward both substrates were inhibited by phenylmethylsulphonyl fluoride and were therefore probably due to a serine peptidase(s). The activities were also inhibited by EDTA and, in a dose-related manner, by alpha 1-antiprotease. Pepstatin, which inhibits cathepsin D, and leupeptin, which inhibits cathepsin B, did not significantly inhibit the elastase-like activities in these cells. The cells were homogenized and a post-nuclear supernatant subjected to sucrose density gradient centrifugation. The distribution of elastase-like activity toward both substrates was similar to that of the plasma membrane marker 5'-nucleotidase, and distinct from those of marker enzymes for the other organelles. Cells were also homogenized with digitonin, which selectively increases the equilibrium density of the plasma membrane. The equilibrium densities of both 5'-nucleotidase and of the elastase-like activities were increased considerably, confirming the plasma membrane localization of the elastase-like activities. The subcellular localization of the elastase-like activities of arterial smooth muscle cells is therefore consistent with a role for them in the degradation of elastin in the normal arterial wall and in atherosclerotic lesions.
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PMID:Properties and subcellular localization of elastase-like activities of arterial smooth muscle cells in culture. 655 16

Total lipids as well as phospholipids extracted from the mitochondrial-lysosomal fraction of porcine adrenal cortex activated the lysosomal cathepsin D of this tissue 30- and 40-fold, respectively, with bovine serum albumin as the substrate. Phosphatidic acid, phosphatidyl ethanolamine, phosphatidyl serine, phosphatidyl inositol, phosphatidyl glycerol and cardiolipin were found to activate greatly the cathepsin D. The degree of activation ranged from 6-fold by phosphatidyl ethanolamine to 40-fold by cardiolipin at 1 mM, respectively. These results strongly point to the importance of phospholipids in intracellular protein degradation by lysosomal cathepsin D.
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PMID:Phospholipids activate cathepsin D. 683 61

Although changes in proteolysis in muscle tissue are now well documented for a variety of physiological and pathological conditions, the mechanism of degradation of cellular protein during normal protein turnover remains to be elucidated. Data from several laboratories have suggested the involvement of alkaline serine proteinases. Recent studies have questioned these results, and demonstrated that the serine proteinases are of mast cell origin and are not present in muscle cells. The only proteinases to date that have been shown to be present in muscle cells and capable of degrading myofibrillar proteins are Ca2+-activated proteinase, cathepsin B, and cathepsin D. Recent interest and developing awareness of endogenous enzyme inhibitors in cells may unmask many new enzymes.
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PMID:Proteinases in cardiac and skeletal muscle. 698 69

Leucocytes and spleen contain four different types of protein proteinase inhibitors. Two of them can be inactivated by cathepsin D. In this work biochemical and immunological studies of the inactivation of I-2 by cathepsin D are presented. Polyacrylamide gel electrophoretic examinations indicate that cathepsin D inactivates I-2 by hydrolysis of the inhibitor molecule. The conversion of the active inhibitor into inactive protein proceeds catalytically. The studies on the inhibitor mechanism of the isoinhibitors of I-1 type explain the unusual inhibitor property of this type of inhibitor to inhibit two different types of proteinases, cysteine and serine. The evidence suggests that the inhibitory mechanism is based on an active sulfhydryl group of the inhibitor which may interact with the disulfide bridge of the inhibited proteinase.
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PMID:Some further characteristics of endogenous proteinase inhibitors. 705 4

In vivo proteolytic modification of liver aldolase on administration of leupeptin, a thiol proteinase inhibitor of microbial origin, is reported. When leupeptin was injected into rats, the activity of aldolase in the liver decreased to 40% of that in control rats. Molecular properties of aldolase isolated from the livers of control rats and leupeptin-treated rats indicated that a decrease of aldolase activity is attributable to hydrolysis of a peptide linkage(s) near the carboxyterminal of the enzyme. Injection of leupeptin also caused marked increase in the activities of free lysosomal proteinases, such as cathepsin A and cathepsin D and moderate increase of cathepsin B and cathepsin L. Increase in free activity of cathepsin A returned to the level of control rats by 12 hr after injection of leupeptin, whereas 36 hr was required for recovery of decreased aldolase activity. When insulin was coinjected with leupeptin, increase in the activity of free cathepsin A and decrease of activity of aldolase produced by the injection of leupeptin was prevented. These findings indicate that modification of aldolase may be due to action of a lysosomal protease(s). Incubation of the purified aldolase with the lysosomal fraction produced the same changes in properties of aldolase as those observed in vivo on injection of leupeptin. The aldolase inactivating proteinase in the lysosomal fraction was inhibited by PMSF and leupeptin and not by pepstatin. Purified cathepsin A (a serine proteinase), cathepsin B and cathepsin L (thiol proteinase) are potent inactivators of aldolase but cathepsin H and cathepsin D are not. Cathepsin A, B and L are involved in inactivation of aldolase in lysosomes. Endogenous thiol proteinase inhibitor which inhibits lysosomal thiol proteinases (cathepsin B, L and H) is found in the cytosol fraction of liver. The level of thiol proteinase inhibitor actually decreased to 60% of that in control rats in leupeptin-treated rats, suggesting that non-thiol proteinase cathepsin A is a major factor in inactivation of aldolase in lysosomes. Not only leupeptin but also other proteinase inhibitors (antipain, E-64-D, chloroquine) caused increase of labilization of the lysosomes and decrease in aldolase activity. Physiological stimuli which are known to induce the labilization of the lysosomal membrane, such as starvation and glucagon, caused slight or no significant increase of activities of free cathepsin A and D and resulted in no apparent change in aldolase activity.
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PMID:Modification of rat liver fructose biphosphate aldolase by lysosomal proteinases. 705 71

Proteolytic processing of neuropeptide precursors is required for production of active neurotransmitters and hormones. In this study, a chromaffin granule (CG) aspartic proteinase of 70 kDa was found to contribute to enkephalin precursor cleaving activity, as assayed with recombinant ([35S]Met) preproenkephalin. The 70-kDa CG aspartic proteinase was purified by concanavalin A-Sepharose, Sephacryl S-200, and pepstatin A agarose affinity chromatography. The proteinase showed optimal activity at pH 5.5. It was potently inhibited by pepstatin A, a selective aspartic proteinase inhibitor, but not by inhibitors of serine, cysteine, or metalloproteinases. Lack of inhibition by Val-D-Leu-Pro-Phe-Val-D-Leu--an inhibitor of pepsin, cathepsin D, and cathepsin E--distinguishes the CG aspartic proteinases from classical members of the aspartic proteinase family. The CG aspartic proteinase cleaved recombinant proenkephalin between the Lys172-Arg173 pair located at the COOH-terminus of (Met)enkephalin-Arg6-Gly7-Leu8, as assessed by peptide microsequencing. The importance of full-length prohormone as substrate was demonstrated by the enzyme's ability to hydrolyze 35S-labeled proenkephalin and proopiomelanocortin and its inability to cleave tri- and tetrapeptide substrates containing dibasic or monobasic cleavage sites. In this study, results provide evidence for the role of an aspartic proteinase in proenkephalin and prohormone processing.
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PMID:Characteristics of the chromaffin granule aspartic proteinase involved in proenkephalin processing. 756 75

We here ascertain whether tryptase (a serine endoprotease released by mast cells) and cathepsin D (CD, a lysosomal hydrolase that seems able to derange the extracellular matrix) play a part in peptic ulcer disease and whether they are linked to Helicobacter pylori (Hp) infection. We studied 13 controls, 25 patients with gastric ulcer, 47 with duodenal ulcer, and 11 with duodenitis. Tryptase and CD were measured in mucosal biopsies (body and antrum of the stomach and duodenum) using IRMA methods. Hp infection was histologically evaluated (Giemsa). Tryptase and CD levels were higher (25%) in patients with active peptic ulcer, whether gastric or duodenal. In Hp-positive patients the CD mucosal content was higher while tryptase mucosal levels were lower than in Hp-negative patients. Tryptase was correlated with gastrin content. CD seems to be mainly related to the phlogistic reaction of the mucosa to Hp infection; tryptase may reflect an indirect link between Hp infection, gastrin release, and the function of mast cells.
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PMID:Influence of Helicobacter pylori on tryptase and cathepsin D in peptic ulcer. 758 35

The pathogenesis of peptic ulcer is a complex phenomenon and several factors are thought to be involved in this process. Among others, Helicobacter pylori infection, hypergastrinaemia and some proteases seem to play an essential role in inducing peptic ulceration. We investigated whether tryptase (a serine endoprotease released by mast cells) and cathepsin D (a lysosomal hydrolase which seems able to derange the extracellular matrix) play a part in peptic ulcer disease and whether they are linked to Helicobacter pylori infection and mucosal content of gastrin. We studied 13 controls, 25 patients with gastric ulcer, 47 with duodenal ulcer and 11 with duodenitis. Tryptase and cathepsin D were measured in mucosal biopsy specimens (body and antrum of the stomach and duodenum) using IRMA methods. Gastrin was assayed in the antral mucosa by means of a RIA method. Helicobacter pylori infection was histologically evaluated (Giemsa). Tryptase and cathepsin D levels were higher (25%) in patients with active peptic ulcer, whether gastric or duodenal. The mucosal content of cathepsin D, but not that of tryptase, was associated with Helicobacter pylori infection. Tryptase, on the other hand, was related to gastrin content. No correlation was found between the two enzymes. It is concluded that tryptase and cathepsin D probably reflect different pathophysiological modifications in ulcer disease. Cathepsin D seems to be mainly related to the phlogistic reaction of the mucosa to Helicobacter pylori infection; tryptase may reflect and indirect link between the action of gastrin and the function of mast cells.
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PMID:Are tryptase and cathepsin D related to Helicobacter pylori infection and mucosal gastrin in peptic ulcer? 820 35

Plasma cells secrete IgM only in the polymeric form: the C-terminal cysteine of the mu heavy chain (Cys575) is responsible for both intracellular retention and assembly of IgM subunits. Polymerization is not quantitative, and part of IgM is degraded intracellularly. Neither chloroquine nor brefeldin A (BFA) inhibits degradation, suggesting that this process occurs in a pre-Golgi compartment. Degradation of IgM assembly intermediates requires Cys575: the monomeric IgMala575 mutant is stable also when endoplasmic reticulum (ER) to Golgi transport is blocked by BFA. Addition of the 20 C-terminal residues of mu to the lysosomal protease cathepsin D is sufficient to induce pre-Golgi retention and degradation of the chimeric protein: the small amounts of molecules which exit from the ER are mostly covalent dimers. By contrast, when retained by the KDEL sequence, cathepsin D is stable in the ER, indicating that retention is not sufficient to cause degradation. Replacing the C-terminal cysteine with serine restores transport through the Golgi. As all chimeric cathepsin D constructs display comparable protease activity in vitro, their different fates are not determined by gross alterations in folding. Thus, also out of its normal context, the mu chain Cys575 plays a crucial role in quality control, mediating assembly, retention and degradation.
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PMID:Quality control of ER synthesized proteins: an exposed thiol group as a three-way switch mediating assembly, retention and degradation. 822 84

The human 46-kDa mannose 6-phosphate receptor (MPR46) is phosphorylated in its cytoplasmic domain at serine residues. Substitution of cytoplasmic serines (at positions 35 and 56) with alanine, expression of mutant receptors in baby hamster kidney cells, and phosphopeptide mapping revealed that serine 56 is phosphorylated. Mutant MPR46 and wild-type MPR46 were found to be similarly distributed between the cell surface and intracellular membranes. Phosphate incorporation in the presence of cycloheximide indicates that phosphorylation occurred on pre-existing MPR46. Similar half-lives for the wild-type and mutant receptor proteins (approximately 43 h) and the receptor-associated phosphate (1.4 h) were found. The mutant receptors were internalized at the same rate as the wild-type receptors. Expression of mutant MPR46 and wild-type MPR46 in mouse L-cells deficient in 300-kDa mannose 6-phosphate receptors did not affect the sorting of newly synthesized cathepsin D to lysosomes. Phosphorylation of cytoplasmic serine 56 is therefore essential neither for stability nor for cell-surface expression and transport activities of MPR46.
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PMID:Phosphorylation of the human 46-kDa mannose 6-phosphate receptor in the cytoplasmic domain at serine 56. 834


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